Transdermal Delivery

ABSTRACT

Dosing regimen for transdermal delivery of hormones comprising a variable treatment cycle and a variable rest interval.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 13/123,026, filedJul. 1, 2011, which is a national entry pursuant to 35 U.S.C. §371 ofPCT/US2009/059828, filed Oct. 7, 2009, which claims benefit of U.S.Provisional Application No. 61/103,757, filed Oct. 8, 2008, the entirecontents of each of which are incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to the field of transdermal delivery, inparticular, of hormones.

BACKGROUND OF THE INVENTION

Progestins, or combinations of progestins and estrogens, are used toinhibit ovulation, and to induce other physiological changes in thefemale reproductive system, and thereby to reduce the risk of pregnancy.

Various dosing regimens have been used to administer such hormones.These include for example, self-administration by oral delivery of aprogestin and an estrogen for 21 days, followed by a 7 day “rest”interval, during which the woman typically experiences withdrawal (i.e.,menstrual) bleeding. Other dosing regimens can also be used, includingdosing regimens that involve longer durations of administration of aprogestin and dosing regimens that involve use of low dose hormoneduring a non-treatment interval.

An important aspect of any effective contraceptive dosing regimen isthat the regimen is convenient so as to facilitate compliance and thatthe doses delivered are effective to prevent or reduce the risk ofpregnancy without exposing the woman to unnecessary risks of sideeffects. Side effects can include hormone-related adverse events andcycle control irregularities, particularly “breakthrough” bleeding.

A transdermal hormone delivery device for administering a progestin andan estrogen via a patch, and a skin permeation enhancer combination foruse therein, are disclosed, e.g., in U.S. Pat. No. 7,045,145 and U.S.20040054901, both of which are incorporated herein by reference asthough fully set forth.

SUMMARY OF THE INVENTION

The instant invention provides a flexible dosing regimen foradministration of a progestin and, optionally, an estrogen. Morespecifically, the invention relates to a method of preventing pregnancy,i.e., reducing the risk of pregnancy, in a woman that comprises,transdermally administering an effective amount of a progestin and,optionally, an estrogen, over a variable treatment interval, followed bya variable rest interval, whereby the length of each treatment intervaland of each rest interval can be varied throughout the course oftreatment, i.e., throughout the duration of time when the woman isundergoing contraception.

In illustrative embodiments, the invention provides a method ofinhibiting conception, i.e., preventing (reducing the risk of)pregnancy, in a woman that comprises:

-   -   (A) consecutively applying multiple transdermal hormone delivery        treatment devices to the skin of the woman during an extended        treatment interval, i.e., greater than 4 weeks, e.g., at least        about 4½ weeks, each device delivering an effective amount of a        progestin and, optionally, of an estrogen, followed by a rest        interval that typically is up to about 7 days, e.g., 3½ or 7        days; and    -   (B) optionally applying a rest interval device during at least a        portion of the rest interval, wherein the rest interval device        comprises (i) low dose progestin, (ii) low dose estrogen, (iii)        low dose progestin and low dose estrogen, or (iv) no hormone.

In more specific illustrative embodiments, the method comprisesconsecutively applying transdermal hormone delivery devices, eachintended for wear for ½ week; the treatment interval is 4½, 5, 5½, 6,6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½,15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½,23, 23½, 24, 24½, 25, 25½, or 26 weeks; and the rest interval is, e.g.,½ week or 1 week.

In other illustrative embodiments, the method comprises consecutivelyapplying transdermal hormone delivery devices, each intended for wearfor 1 week; the treatment interval is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 8, 19, 20, 21, 22, 23, 24, 25, or 26 weeks; and the restinterval is, e.g., ½ week or 1 week.

If a treatment interval is only 3 weeks, such that the rest intervalwould exceed about 7 days, particularly if the rest interval wouldexceed 8 days or would exceed 9 days, then a rest interval devicecomprising low dose hormone would typically be used during all or atleast a portion of the rest interval, as illustrated, e.g., by FIG. 1 d.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1a, 1b, 1c and 1d (also referred to interchangeably herein as FIG.1a , FIG. 1b , FIG. 1c and FIG. 1d ) illustrate hormone serumconcentrations during and after a single treatment cycle comprising atreatment interval of 21 or 24½ days with or without a hormonecontaining patch in the rest interval. The figures have been drawn to 31days for illustrative purposes only and do not illustrate hormone serumconcentrations during a succeeding treatment cycle. FIG. 1a illustratesEE serum concentration levels over 31 days resulting from administrationof 7 patches each for 3½ days. FIG. 1b illustrates EE serumconcentration levels over 31 days resulting from administration of 7patches each for 3½ days, followed by administration of a rest intervaldevice (½ patch) for 3½ days. FIG. 1c illustrates EE serum concentrationlevels over 31 days resulting from administration of 3 patches each for7 days. FIG. 1d illustrates EE serum concentration levels over 31 daysresulting from administration of 3 patches each for 7 days, followed byadministration of a rest interval device (½ patch) for 7 days.

FIG. 2 illustrates an exploded cross-section of an illustrative dermaldelivery system of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with illustrative embodiments of the present invention, asingle treatment interval, during which a woman is treated bytransdermally administering to the woman an effective amount of aprogestin and, optionally, an estrogen, is variable.

By “variable,” is meant that the duration of each treatment interval canbe varied by the user during the period during which contraception isdesired. For example, a woman may elect at any time to allow herself tomenstruate by suspending use of treatment devices at any time, e.g.,because she is experiencing breakthrough bleeding or because for otherreasons she wants to allow her body to proceed through menses or wantsto reduce the likelihood that she will experience bleeding at a giventime. For example, if a woman is planning a vacation, she may elect toinitiate a rest interval sufficiently in advance of the vacation to makeit unlikely that she will experience menstrual bleeding. Thus,“variable” can mean adjusting the duration of a treatment interval so asto avoid (i.e., minimize the chances of) menstrual bleeding during agiven time interval.

A treatment interval is typically 21 days or longer. In someembodiments, the treatment interval is extended and flexible. By“extended,” is meant that the treatment interval is extended beyond fourweeks.

Thus, this invention provides a woman with flexibility to decide, withinsafe and effective bounds, how long a given treatment interval shouldbe, how long a given rest interval should be (if any), whether or not touse a rest interval device during a given rest interval and, if so, forwhat part of the rest interval, etc.

For example, in a given treatment cycle comprising a treatment intervaland a rest interval, a woman can decide to enter a rest interval of 1 toabout 7 days after a treatment interval of 21 days. In accordance withthis invention, the woman would ordinarily not choose successive 21 daytreatment intervals. For example, she may then decide that thesucceeding treatment interval will end after a different number of days,e.g., 43 days, to be followed by a rest interval of the same or adifferent number of days as the previous rest interval. Succeedingtreatment intervals can be of longer or shorter duration as previoustreatment intervals and succeeding rest intervals can be of longer orshorter duration than previous rest intervals. In other words, it is notnecessary that each treatment interval be of the same duration as theprevious ones or that each rest interval be of the same duration as theprevious ones.

In an alternative, each treatment interval can be a minimum of 4½ weeks,or a minimum of 9 weeks, e.g., 3 or 6 months.

In another alternative, a woman may find it more convenient to stay on aregular schedule for a length of time, whereby each treatment intervalis the same length of time and is at least 4½ weeks, or at least about 9weeks, e.g., 3 months or 6 months, and each rest interval is of the samelength of time as other rest intervals.

In some embodiments of the invention, the rest interval is 0 days, i.e.,a treatment device is worn throughout the period of time during whichcontraception is desired. This is typically the case when the treatmentdevice comprises a progestin without an estrogen.

The woman may also choose to vary whether or not she uses a restinterval device and, if so, for what part of the rest interval. She mayalso have the option of choosing whether or not the rest interval deviceis a placebo or contains a low dose of a progestin, a low dose of anestrogen, or a low dose of both a progestin and an estrogen. By “lowdose” is meant a dose that is not effective for contraception if usedthroughout a treatment interval.

Conveniently, transdermal delivery is accomplished by means oftransdermal hormone delivery devices, i.e., “patches,” that are wornconsecutively throughout the treatment interval, for a wear interval of½ week or 1 week.

Each ½ week period is about 3 to about 4 days. For example, a single½-week device can be worn for 2½ or 3 days of a given week, in whichcase the other ½-week device would be worn for 4½ or 4 days of thatweek, respectively, or each device can be worn for 3½ days each. Eachone week period can similarly be 6, 6½, 7½, and 8 days, although it ispreferable to fix one day per week such that a week is 7 days.

In illustrative embodiments that employ ½ week patches, each treatmentinterval can independently be 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10,10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18,18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, or26 weeks, or longer.

In illustrative embodiments that employ 1 week patches, each treatmentinterval can independently be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 8, 19, 20, 21, 22, 23, 24, 25, or 26 weeks, or longer.

In any event, at the end of each treatment interval, there follows arest interval that is variable and would typically be ½ week or 1 week.So, for example, if the treatment interval is 12 weeks, as in the caseof 12 devices each worn for one week, or 24 devices each worn forone-half week, the rest interval would likely be ½ week or 1 week,although it could be varied shorter or longer. While a rest interval ofup to 7 days is typical, the rest interval can also be extended, e.g.,to 10, 12, or 14 or more days. In such cases, it may be advantageous toadminister low dose hormone during all or a portion of the extended restinterval. At the other end, a rest interval can be as little as a singleday or two days but is more typically at least 3 days, e.g., 3, 4, 5, 6,or 7 days. A woman can choose, e.g., to have a rest interval from 1 upto about 12 times per year.

A woman may choose to begin wearing the first patch of the firsttreatment interval on, or about on, the first day of the woman's period,i.e., on the first day of menstrual bleeding. In this case, the womancan employ a longer or shorter initial treatment interval or initialrest interval, in order to get her on to a schedule that is convenientfor her.

In embodiments of the invention, only a progestin is administered duringtreatment intervals. In other embodiments, the progestin is administeredin combination with an estrogen during treatment intervals, for all or aportion of each treatment interval. In either case, a progestin or anestrogen or both can but is not necessarily administered during all or aportion of the rest interval, as described below.

The amount of hormone in each treatment device, e.g., each 3½ day patchor 7 day patch, can be varied from patch to patch, or week to week, toprovide a multiphasic treatment regimen. For example, the amounts ofhormone can be varied so as to provide a triphasic delivery regimen suchas, e.g., the triphasic oral contraceptive disclosed in U.S. Pat. No.6,214,815 (Ortho-McNeil). Either or both of the progestin and theestrogen can be varied (or maintained) independently of each other.Alternatively, the amount of the progestin and of the estrogen can bethe same in all patches used in a given treatment cycle or in alltreatment cycles.

It is desirable that each treatment device result in an averageprogestin serum concentration level equivalent to at least about 750pg/ml of levonorgestrel during the entire treatment interval. In someembodiments, the average progestin serum concentration level isequivalent to at least about 500 pg/ml of levonorgestrel during week 1of the treatment interval and/or is at least about 750 pg/ml during week2 and week 3 of each treatment interval, it being understood, however,that such levels may not be achieved during the entire first treatmentcycle. In particular, for example, such levels may not be achievedduring the first week of the first treatment cycle.

In addition, serum concentrations of a progestin, as well as of anestrogen, can vary from patient to patient. Thus, when consideringaverage serum concentrations achieved during treatment intervals, it isuseful to refer to a population of subjects, e.g., 10 or more, 25 ormore, 50 or more, 75 or more, or 100 or more. Thus, the concentrationvalues, and peak-trough relationships, expressed herein may be achievedin a population of subjects but not necessarily in every subject withina given population.

The amount of estrogen delivered during each treatment interval can bean amount that results in serum concentration levels equivalent to about5 to about 80, e.g., about 15 to about 65, pg/ml of ethinyl estradiolduring the entire treatment interval, or about 20 to about 30 pg/ml.Serum concentration levels that average about 20 to about 30 pg/mlethinyl estradiol equivalent can be achieved during week 2 and week 3 ofeach treatment interval.

In an illustrative embodiment of the invention, low (or lower) dosehormone(s) can be delivered during all or a part of the rest interval.The amount of hormone delivered during the rest interval is no more thanabout 80%, e.g., about 20% to about 80%, of the amount delivered duringthe treatment interval. For example, the amount of hormone(s) deliveredduring the rest interval can be about ¾, about ⅔, about ½, about ⅓, orabout ¼ of the amount delivered during an equivalent amount of timeduring the treatment interval. Such amount may attenuate, i.e., lessenthe severity of, symptoms of menstruation, which can include excessivevaginal bleeding, mood changes, headaches, dysmenorrhea and othersymptoms associated with hormone withdrawal, especially sudden hormonewithdrawal, or otherwise.

Such rest interval patch, or rest interval device, can conveniently bemade in the same manner as the treatment device but with a reducedamount of hormone(s). The amount of hormone(s) can be reduced, forexample, by reducing the size of the patch. For example, if a treatmentpatch has a surface area of 20 cm² and it is desired to deliver 50% ofthe hormones during the rest interval, then the rest interval device canbe the same as the treatment interval device but reduced in size to havea surface area of 10 cm². Such rest interval device could be referred toas a “half patch.” Similarly, one could administer a “quarter patch” todeliver 25% of the hormones, or a patch of any other fraction of thesize of the treatment patch. Alternatively, the size (surface area) ofthe rest interval device can be the same as the size of the treatmentdevice, in which case it would be loaded with reduced amounts ofhormones and/or enhancers.

The rest interval device can be worn for any part or the whole of therest interval. So, for example, a half patch can be worn for the fullrest interval.

FIGS. 1a, 1b, 1c and 1d show illustrative hormone serum concentrationlevels over 31 days. In accordance with the practice of this invention,of course, a fresh device can be applied on Day 29.

As illustrated in FIGS. 1a, 1b, 1c and 1d , patches can be designed soas to deliver varying amounts of hormone(s) during the period of wear ofeach patch, such that there is a peak serum concentration level thatoccurs after the patch is applied and a trough serum concentration levelthat occurs at the time the patch is removed. This characteristic can beusefully employed to deliver an amount of a progestin or an estrogen, orboth, during the rest interval that declines as the end of the restinterval approaches such that the amount of hormone delivered by the endof the rest interval is decreased relative to peak levels during wear ofthe rest interval device and, in some embodiments, relative to serumconcentration levels on the day that the rest interval device isapplied. Such device can be referred to as a descending dose device.

Use of such rest interval device can have several advantages. In oneembodiment, the rest interval device is a placebo and is used as amatter of convenience, e.g., so that the woman stays in the habit ofremoving and applying a patch every 3-12 days or every 7 days. Inanother embodiment, low dose hormone is delivered such that the womanexperiences menstruation but with attenuated symptoms. In suchembodiment, also, hormone serum concentration levels are adjustedgradually rather than “all or nothing”.

A 3½ day patch can be smaller than a 7 day patch therefore making itless noticeable to the wearer and persons around her. The adhesivenessrequirements are also eased because the patch is smaller and because itdoesn't need to stay attached for a full week. If a 3½ day patch doesbecome dislodged, there will only be a short period of time before thenext patch is due to be applied. A 3½ day patch can allow for apharmacokinetic (PK) profile having peaks and troughs during each wearperiod, i.e., during each 3½ day period of treatment, but such peaks andtroughs can be smoother relative to a 7 day patch. So, for example, peakhormone serum concentrations during the period of time in which a singletreatment device (other than the first device) is worn can be at leastabout 1.1 times trough levels, or at least about 1.25 times the troughlevels, but also can be no more than about twice the trough levels, orno more than about 1.8 times the trough levels, or no more than about1.5 times the trough levels. FIGS. 1a, 1b, 1c and 1d illustrate suchpeak-trough PK profiles. Such PK profile can be achieved during anentire treatment interval or during at least a single wear interval,e.g., the third week, the second half of the second or third weeks, orat least 2 weeks, e.g., the second and third weeks, of each treatmentinterval.

Any transdermal hormone delivery device that delivers a progestin and,optionally, an estrogen, in amounts effective to effect contraception,i.e., to prevent pregnancy, can be used in the practice of theinvention. “Preventing pregnancy” does not necessarily mean that suchdevices are 100% effective in preventing pregnancy in all cases but suchdevices can have, at least, approximately the same contraceptiveefficacy as currently available oral contraceptives. A transdermalhormone delivery device for preventing pregnancy that delivers17-deacetyl norgestimate and ethinyl estradiol is disclosed in U.S. Pat.No. 5,876,746 (Cygnus) and is marketed as Ortho Evra(r)(norelgestromin/ethinyl estradiol transdermal system). As shown in theprescribing information, Ortho Evra provides a more or less “flat”delivery, i.e., no or only a slight peak-trough PK profile for eachperiod of wear of a single patch.

The invention also comprises a kit comprising multiple patches eachintended to be worn for ½ week (2½ to 4½ days) or 1 week (6-8 days). Forexample, such kit may comprise nine or more ½ week treatment devices.Or, for example, such kit may comprise five or more 1 week treatmentdevices. Or, for example, such kit may comprise a combination of ½ weekand 1 week devices. In each case, the kit would include instructions foruse of the devices in accordance with the method of the invention.

Such kit can also comprise rest interval devices, which can be placebos(i.e., no hormone) or low dose hormone devices, as discussed above. Forexample, a kit that comprises 24½-week treatment devices may comprise upto 4 rest interval devices, whereby, at one end of the spectrum oftreatment options, a woman may use all treatment devices without everusing a rest interval device or, at the other end of the spectrum, shemay use all of the rest interval devices, each one for up to about aweek and each one typically following a treatment interval of 21 days.In each case, the kit would include instructions for use of the devicesin accordance with the method of the invention. Such kit would compriseinstructions explaining the options for variable and extended use.Typically, such kit would be designed on the assumption that eachtreatment interval would be at least 4½ weeks. In certain embodiments,each rest interval device comprises (i) low dose progestin, (ii) lowdose estrogen, or (iii) low dose progestin and low dose estrogen.

Such rest interval devices can be clearly indicated as rest intervaldevices, directly or on individual patch packaging, such as by size,color, shape, or markings, to avoid confusion with treatment devices. Ifa multiphasic hormone delivery profile is desired, then each treatmentdevice can be marked, directly or on individual patch packaging, tominimize the risk that a user will apply patches out of order.

FIGS. 1a, 1b, 1c and 1d illustrate projected serum concentration levelsof ethinyl estradiol (EE) resulting from administration of patches suchas described in U.S. Pat. No. 7,045,145 and U.S. 20040054901 andhereinbelow.

The data in FIGS. 1a, 1b, 1c and 1d are illustrative and do not show theeffect of applying a new patch on Day 29. The data are projectionscalculated on the basis of actual human cadaver skin flux data obtainedusing a device loaded with a polymeric matrix comprising LNG and EE,substantially as described below, and having a skin contact area ofapproximately 9.4 cm². The projections are calculated using anapproximate in vivo clearance rate for EE. FIGS. 1a and 1b show EElevels on each of Days 1 through 28, with a first 3½ day patch beingapplied on Day 0 and subsequent patches being applied on Days 4, 7, 11,14, 18, and 21. FIGS. 1c and 1d show EE levels on each of Days 1 through28, with a first 7 day patch being applied on Day 0 and subsequentpatches being applied on Days 7 and 14. FIGS. 1b and 1d show the effectsof administering a rest interval patch on Days 24-28, said rest intervaldevice being V2 the size of but otherwise identical to, the treatmentpatch.

A similar pattern of peaks/troughs can be obtained with progestins,e.g., LNG.

Note that because these data are projected from skin flux data, actualresults will vary, depending, e.g., upon the skin surface area of thepatch employed, the concentration of hormone(s), and the efficacy of theskin permeation enhancer.

An illustrative device that can be used in the practice of the instantinvention is illustrated in FIG. 2.

With reference to FIG. 2, this illustrative device comprises 4 layers.One is the AI layer (6). The second is a release liner (4). The third isan internal backing layer (5). The fourth is an overlay, which in thisillustrative device, itself comprises three component layers (1, 2, 3),referred to herein below as, respectively, a PSA layer (3), anintermediate layer (2), and an overlay covering or overlay coating (1).The overlay can also be described as comprising a PSA layer (3) and anoverlay covering (1, 2). In any event, a feature of this device isformation of a seal between the PSA layer (3) of the overlay (1, 2, 3)and the release liner (4).

The AI Layer

Layer 6 comprises the AI and carriers comprising skin permeationenhancers, a humectant/plasticizer, and a PSA matrix. The AI comprise aprogestin, e.g., levonorgestrel, and an estrogen, e.g., ethinylestradiol or 17-n estradiol.

Skin Permeation Enhancers:

A combination of skin permeation enhancing agents is employed thatcomprises a mixture of (1) a pharmaceutically acceptable organicsolvent, such as dimethyl sulfoxide (DMSO), (2) a fatty (C8-C20) alcoholester of a hydroxy acid, such as lauryl lactate, (3) a lower (C1-C4)alkyl ester of a hydroxy acid, e.g., ethyl lactate, and (4) a C6-C18fatty acid, such as capric acid. In specific embodiments, the fattyalcohol ester of lactic acid is lauryl lactate and the lower alkyl esterof lactic acid is ethyl lactate. A medium- to long-chain fatty acid inthe skin permeation enhancer formulation can be employed among the skinpermeation enhancers. Capric acid has been used but other C6-C18saturated or unsaturated fatty acids include but are not limited tocaproic acid, caprytic acid, lauric acid and myristic acid.

In a particular such embodiment, the pharmaceutically acceptable organicsolvent is DMSO. Other organic solvents include but are not limited toC1-C8 branched or unbranched alcohols, such as ethanol, propanol,isopropanol, butanol, isobutanol, and the like, as well as azone(laurocapram: 1-dodecylhexahydro-2H-azepin-2-one) andmethylsulfonylmethane.

The fatty alcohol ester of a hydroxy acid can be a fatty alcohol esterof lactic acid, such as lauryl lactate. However, other hydroxy acids andfatty alcohols may be utilized. Alternative hydroxy acids include butare not limited to alpha-hydroxy acids such as glycolic acid, tartaricacid, citric acid, malic acid and mandelic acid, as well as thebeta-hydroxy acid, salicylic acid. Alternative fatty alcohols includeany C8-C20 saturated or unsaturated fatty alcohols, such as myristyl,palmityl or oleyl alcohols, to name a few.

The lower alkyl ester of hydroxy acid can also utilize lactic acid, andcan be, e.g., ethyl lactate. However, other hydroxy acids, such asglycolic acid, tartaric acid, citric acid, malic acid, mandelic acid andsalicylic acid, may also be utilized. In addition isopropylmyristic acid(IPM) may be used as a substitute for the lower alkyl ester of hydroxyacid.

Hormones:

LNG is a potent progestin on a weight-dose basis, which is an importantfactor since progestins often exhibit a much lesser degree oftransdermal absorption than do estrogens. Other progestins that could beused in part or total are norgestrel, norgestimate, desogestrel,gestodene, norethindrone, nore-thynodrel, hydrogesterone, ethynodioldicetate, hydroxyprogesterone caproate, medroxyprogesterone acetate,norethindrone acetate, progesterone, megestrol acetate, gestogen andcertain others which are biocompatible and absorbable transdermally.These include biocompatible derivatives of progestins that aretransdermally absorbed, some of which, advantageously, arebioconvertible after transdermal absorption to the original progestin.The progestin and other hormones selected preferably have highcompatibility with each other.

For combinations of progestin with estrogen, the synthetic hormone EE isparticularly suitable, although natural estrogen or other analogs can beused. This hormone may be transdermally delivered in conjunction withthe particularly suitable progestin, levonorgestrel, at desirable dailyrates for both hormones. EE and LNG are compatible and can be dispersedin the adhesive polymer formulation.

Derivatives of 17 β-estradiol that are biocompatible, capable of beingabsorbed transdermally and preferably bioconvertible to 17 β-estradiolmay also be used, if the amount of absorption meets the required dailydose of the estrogen component and if the hormone components arecompatible. Such derivatives of estradiol include esters, either mono-or di-esters. The monoesters can be either 3- or 17-esters. Theestradiol esters can be, illustratively speaking,estradiol-3,17-diacetate; estradiol-3-acetate; estradiol 17-acetate;estradiol-3,17-divalerate; estradiol-3-valerate; estradiol-17-valerate;3-mono-, 17-mono- and 3,17-dipivilate esters; 3-mono-, 17-mono- and3,17-dipropionate esters; 3-mono-, 17-mono- and3,17-dicyclopentyl-propionate esters; corresponding cypionate,heptanoate, benzoate and the like esters; ethinyl estradiol; estrone;and other estrogenic steroids and derivatives thereof that aretransdermally absorbable.

Combinations of the above with estradiol itself (for example, acombination of estradiol and estradiol-17-valerate or further acombination of estradiol-17-valerate and estradiol-3,17-divalerate) canbe used with beneficial results. For example, 15-80% of each compoundbased on the total weight of the estrogenic steroid component can beused to obtain the desired result. Other combinations can also be usedto obtain desired absorption and levels of 17 β-estradiol in the body ofthe subject being treated.

It will be appreciated that the hormones may be employed not only in theform of the pure chemical compounds, but also in a mixture with otherpharmaceuticals that may be transdermally applied or with otheringredients which are not incompatible with the desired objective aslisted above. Thus, simple pharmacologically acceptable derivatives ofthe hormones such as ethers, esters, amides, acetals, salts and thelike, if appropriate, may be used. In some cases, such derivatives maybe preferred. The progestin compound and the estrogenic steroid areordinarily dispersed or dissolved concurrently in fabricating thehormone-containing adhesive polymer matrix or they may be dispersed ordissolved separately.

Polymers Used as Active Patch Components:

The AI-containing layer can be a polymer matrix comprising thepharmaceutically or cosmetically active ingredient. The polymer can be aPSA to form a biologically acceptable adhesive polymer matrix,preferably capable of forming thin films or coatings through which theAI can pass at a controlled rate. Suitable polymers are biologically andpharmaceutically compatible, nonallergenic, insoluble in and compatiblewith body fluids or tissues with which the device is contacted. The useof water soluble polymers is generally less preferred since dissolutionor erosion of the matrix would affect the release rate of the AI as wellas the capability of the dosage unit to remain in place on the skin. So,in certain embodiments, the polymer is non-water soluble.

Preferably, polymers used to form a polymer matrix in the AI-containinglayer have glass transition temperatures below room temperature. Thepolymers are preferably non-crystalline but may have some crystallinityif necessary for the development of other desired properties.Cross-linking monomeric units or sites can be incorporated into suchpolymers. For example, cross-linking monomers that can be incorporatedinto polyacrylate polymers include polymethacrylic esters of polyolssuch as butylene diacrylate and dimethacrylate, trimethylol propanetrimethacrylate and the like. Other monomers that provide such sitesinclude allyl acrylate, allyl methacrylate, diallyl maleate and thelike.

In certain transdermal drug delivery devices, there is a permeable orrupturable barrier, rate controlling membrane, or the like interposedbetween the AI-containing material and the release liner such that whenthe release liner is removed, said barrier remains in place. The purposeof such barrier can be, e.g., to prevent the AI-containing material fromflowing out of the device or to control the rate of absorption by theskin. In the device used to generate the data illustrated in FIGS. 1a,1b, 1c and 1d , there is no need for a layer between the release linerand the AI layer because the polymer matrix is adhered to the remaininglayers of the device and does not readily flow and because the matrix isdesigned to deliver adequate drug across the skin without a need torestrict the flow rate. Thus, the polymer matrix is adhered directly tothe release liner and, upon administration to the skin, the polymermatrix is adhered directly to the skin across the entire surface area ofthe AI layer exposed by removal of the release liner.

A useful adhesive polymer formulation comprises a polyacrylate adhesivepolymer of the general formula (I):

wherein “X” represents the number of repeating units sufficient toprovide the desired properties in the adhesive polymer and R is H or alower (C1-C10) alkyl, such as ethyl, butyl, 2-ethylhexyl, octyl, decyland the like. More specifically, it is preferred that the adhesivepolymer matrix comprises a polyacrylate adhesive copolymer having a2-ethylhexyl acrylate monomer and approximately 50-60% w/w of vinylacetate as a co-monomer. An example of a suitable polyacrylate adhesivecopolymer for use in the present invention includes, but is not limitedto, that sold under the tradename of Duro Talc 87-4098 by NationalStarch and Chemical Co., Bridgewater, N.J., which comprises a certainpercentage of vinyl acetate co-monomer.

Humectant/Plasticizer:

Preferably, a plasticizer/humectant is dispersed within the adhesivepolymer formulation. Incorporation of a humectant in the formulationallows the dosage unit to absorb moisture from the surface of skin whichin turn helps to reduce skin irritation and to prevent the adhesivepolymer matrix of the delivery system from failing. Theplasticizer/humectant may be a conventional plasticizer used in thepharmaceutical industry, for example, polyvinyl pyrrolidone (PVP). Inparticular, PVP/vinyl acetate (PVP/VA) co-polymers, such as those havinga molecular weight of from about 50,000, are suitable for use in thepresent invention. The PVP/VA acts as both a plasticizer, acting tocontrol the rigidity of the polymer matrix, as well as a humectant,acting to regulate moisture content of the matrix. The PVP/VA can be,for example, PVP/VA S-630 which is a 60:40 PVP:VA co-polymer that has amolecular weight of 51,000 and a glass transition temperature of 110 C.The amount of humectant/plasticizer is directly related to the durationof adhesion of the overlay. The PVP/vinyl acetate can be PVP/VA S-630supplied by International Specialty Products, Inc. (ISP) of Wayne, N.J.,wherein the PVP and the vinyl acetate are each present in approximatelyequal weight percent.

The shape of the device of the invention is not critical. For example,it can be circular, i.e., a disc, or it can be polygonal, e.g.,rectangular, or elliptical. The surface area of the AI layer generallyshould not exceed about 60 cm² in area. Preferably, it will be about 5to 50 cm², more preferably, about 8 to about 40 cm². Most preferably,the discs will be about 10 to about 20 cm². A disc of 15 cm² may bepreferred because it is relatively small but can be capable ofdispersing high levels of hormones.

Thus, an illustrative hormone-comprising polymer matrix useful fordelivering an effective amount of a progestin and of an estrogen inamounts effective to prevent pregnancy in accordance with the method ofthe invention comprises a polyacrylate adhesive copolymer with about 3%to about 60% w/w vinyl acetate and, on a weight percentage basis of theadhesive polymer matrix:

-   -   a) from about 15% to about 35% of PVP/VA;    -   b) from about 10% to about 30% percent of a combination of skin        permeation enhancing agents which is a mixture comprising from        about 4% to about 12% DMSO, from about 4.2% to about 12.6%        lauryl lactate, from about 0.7% to about 2.3% ethyl lactate, and        from about 3% to about 9% capric acid; and    -   c) from about _0.6% to about 1.2% LNG and EE, e.g., about 0.87%        LNG and about 0.77% EE.

The Internal Backing Layer

An internal backing layer can be made of any suitable material that isimpermeable or substantially impermeable to the AI and to excipients ofthe adhesive polymer matrix. The internal backing layer serves as aprotective cover for the AI layer and provides a support function. Thebacking layer can be formed so that it is essentially the same size asthe hormone-containing adhesive polymer matrix or it can be of largerdimension so that it can extend beyond the edges of the AI-containingpatch outwardly. The backing layer can be any appropriate thickness thatwill provide the desired protective and support functions. A suitablethickness is from about 10 to about 300 microns. More specifically, thethickness is less than about 150 microns, yet more specifically, it isless than about 100 microns, and most specifically, the thickness isless than about 50 microns.

Examples of materials suitable for making the internal backing layer arefilms of polypropylene, polyesters such as poly(ethylene terephthalate),metal foils, metal foil laminates of such suitable polymer films, andthe like. Polyester films, such as Mylar® (DuPont Teij in) andScotchpak® 9732 (3M Company), are particularly suitable for use in thepresent invention.

The Release Liner

The surface area of the release liner is greater than that of the AIlayer. This can be seen in FIG. 2, where the diameter (in the case of around device) or width and length (in the case of a polygonal device) ofLayer 3 is greater than that of Layers 5 and 6, such that it extendsbeyond the AI layer in some or all directions.

The release liner is made of any material (1) that is impermeable orsubstantially impermeable to the components of the AI layer, (2) towhich the PSA in the overlay will adhere, as discussed furtherhereinbelow, and (3) that is readily removable by peeling from the AIlayer and overlay PSA just prior to applying to the skin.

The release liner can have the same dimensions as the overlay, discussedbelow, or it can extend totally or partially beyond the edge of thepatch. In one embodiment, the release liner extends partially beyond theoverlay so as to form “tabs” of release liner material that extendbeyond the edges of the overlay for easy separation of the release linerfrom the rest of the system.

It can comprise a fluorinated or siliconized polyester film or anotherfluorinated or siliconized polymer such as a polyacrylonitrilecopolymer, or a foil lined with a siliconized or fluorinated polymer.The release liner is preferably not polystyrene because it has beenshown that polystyrene will absorb DMSO. A preferred material for therelease liner when the layer 4 a of the overlay comprises a PIB PSA is aScotchpak® liner (3M Company), such as Scotchpak® 1022 or Scotchpak®9744 fluorinated polyester release liners.

The Overlay

The overlay comprises a PSA in which the solubility of the volatilecomponents is less, preferably significantly less, than the solubilityof those same components in the AI matrix. So, e.g., when the volatilecomponent is DMSO or ethyl lactate, a PIB PSA may be chosen. Withreference to FIG. 2, the PIB PSA layer is Layer 3. Generally, such PIBPSA comprises a mix of a low to medium molecular weight and a highmolecular weight PIB, a plasticizer such as polybutene, and ahydrocolloid such as a cross-linked polyvinylpyrrolidine. Useful PIBsinclude, e.g., Oppanol® PIBs (BASF), which have average molecularweights of between 40,000 and 4,000,000.

A useful PIB PSA comprises crospovidone such as Kollidon® CLMcrospovidone (BASF) (e.g., 5-45 wt %, preferably 15-30 wt %, and morepreferably 20-25 wt %); a low viscosity PIB such as Oppanol® B12(molecular weight: 51000, viscosity at 150 C: 150 Pascal-seconds) (e.g.,10-60 wt %, preferably 30-50 wt %); a high viscosity PIB such asOppanol® B100 (viscosity: approximately 1100 Pascal-seconds) (e.g., 2-15wt %, preferably 5-15 wt %); a polybutene such as Indopol® 1900(Innovene LLC) (molecular weight: 2500, viscosity at 100 C: 3900-4200centistokes) (e.g., 10-60 wt %, preferably 20-40 wt %); and a mineraloil (0-20 wt %). For example, an illustrative formulation comprisesabout 20 wt % crospovidone, about 40 wt % of a low viscosity PIB, about8 wt % of a high viscosity PIB and about 32 wt % of polybutene. (Theterm, “about,” as used in this specification, means plus or minus 10%.By “low viscosity” is meant less than about 300 Pascal-seconds and by“high viscosity” is meant more than about 800 Pascal-seconds, when theviscosity is measured at 150 C.) Cross-linking of the PVP is usefulbecause such cross-linked polymers tend to be water-swellable but waterinsoluble. Such PIB PSA can provide good wear stability, e.g.,attachment under normal living conditions for at least 7 days.

Other rubber-based polymers that can be used in place of PIB PSA in theoverlay include silicone-based PSAs, such as BIO-PSA® (Dow Corning);copolymers and terpolymers of styrene/butadiene/styrene,styrene/isoprene/styrene, and styrene-ethylene/butylenes-styrene, suchas Kraton D styrene/butadiene and Kraton Gstyrene-ethylene/butylene-styrene or styrene-ethylene/propylene-styrene.Isoprene rubbers, such as Kraton IR linear polyisoprene homopolymers,can also be used.

As shown in FIG. 2, and like the release liner, the overlay can extendbeyond the perimeter of the AI layer in all directions, typically by amargin of about 0.1 to about 1.5 cm, more specifically about 0.3 toabout 1.2 cm, and yet more specifically about 0.8 cm beyond theperimeter of the AI layer.

The overlay, if it comprises a PSA layer, improves adherence to the skinby supplementing the adhesion provided by the PSA in the AI layer, ifpresent, or, in the case of an AI layer that does not comprise a PSA, itprovides adherence to the skin.

In addition, the overlay adheres to the release liner around theperimeter of both layers, thereby sealing in the components of the AIlayer. By properly selecting the materials that comprise the overlay andthe release liner, this seal between them prevents, or substantiallyprevents, escape of the volatile component in the AI layer but stillallows the release liner to be peeled away easily by the user prior totopical application.

The seal is formed in situ by mechanically pressing together the edgesof the overlay that extend beyond the perimeter of the AI layer and theedges of the release liner that extend beyond the perimeter of the AIlayer. When the first overlay layer is a PIB PSA and the release lineris a fluorinated or siliconized polyester film, a suitable seal can bemade by applying pressure. The amount of pressure required to form suchseal is not critical. Finger pressure is adequate. Of course, in anillustrative embodiment of the invention, it is desirable that the sealcan be broken by peeling the release liner from the rest of the systemby hand just prior to application to the skin.

The seal between the overlay PSA and the release liner prevents, orsubstantially prevents, loss of the components of the AI layer throughthe seal between these two layers such as during storage of the system.The seal is preferably “tight” to the internal backing layer and the AIlayer such that there is minimal or no seepage of the polymer matrixinto spaces between the overlay and the release liner or between theoverlay and the internal backing layer or the AI layer.

The overlay can also comprise a covering (1) that does not comprise aPSA, i.e., that comprises a non-PSA layer, such that the surface of theoverlay that is exposed to fingers, clothing and ambient dirt or dust isnon-tacky, is flexible or malleable so as to flex with skin and musclemovements, is of an unnoticeable or attractive color and texture, andpermits moisture from the skin to pass through the device owing to itsbeing porous or otherwise permeable to water.

Thus, it may be desirable to utilize a multi-layered overlay comprisinga first layer of a PSA in which the volatile component is insoluble,covered with an intermediate layer and an overlay covering having theproperties described above. Such illustrative overlay is illustrated inFIG. 2 as Layers 1, 2, and 3.

While a PIB PSA is useful for containing DMSO or ethyl lactate, or both,in the AI layer, the PIB PSA may flow through most overlay coveringshaving the properties described above. Such flow of the PIB PSA cancause the device to become tacky and discolored. Therefore, it may bedesirable to use an overlay covering that itself comprises two layers,one of which is a polymeric layer interposed between the PIB PSA (anintermediate layer) and a backing layer. Such intermediate layer can bea polyacrylate PSA as described above, because such PSA willsubstantially prevent flow of the PIB PSA into and through the overlaycovering but will substantially not itself migrate into or through theoverlay covering.

The overlay is a laminate that comprises three layers: a PIB PSA layer(3, in FIG. 2); an intermediate layer that comprises a material thatdoes not permit flow of the PIB PSA but that does permit passage ofmoisture (2, in FIG. 2); and an overlay covering (or backing layer) thatis non-tacky, attractive, flexible, and moisture permeable (1, in FIG.2).

Materials useful in the intermediate layer include, e.g., polyacrylates,polyurethanes, plasticized polyvinyl chlorides, and copolymers ofpolyethylene and ethyl vinyl acetate. Rubber-based polymers that are ofvery high molecular weight, e.g., at least about 150,000 Daltons canalso be used, as can rubber-based polymers that can be crosslinked.Examples include the Kraton D styrene/butadiene, Kraton Gstyrene-ethylene/butylene-styrene or styrene-ethylene/propylene-styreneand Kraton IR linear polyisoprene homopolymers Butyl rubbers andsilicone rubbers, which are cross-linkable, can also be used. Theintermediate layer can comprise a PSA that binds the first overlay layeras well as the overlay covering. High molecular weight, cross-linkedpolymers are preferred. Preferably, such PSA is a polyacrylate such asis described above with reference to the AI layer.

Materials used in the overlay covering are not PSAs. They include, forexample, a polyurethane film, foam or spun bonded structure, apolyolefin foam, a PVC foam or a woven or non-woven fabric. Illustrativewovens include KOB 051, 053 and 055 woven polyesters (Karl Otto Braun.)Illustrative non-woven fabrics include polyesters. An illustrativepolyurethane material is CoTran™ 9700 melt-blown polyurethane nonwovenbacking (3M), which can be colored in skin tones. Suitable materials aredescribed, e.g., as backing layers in U.S. Pat. No. 6,660,295.

If the overlay covering is not porous, then it can be used without anintermediate layer. However, if the overlay covering is not porous,adhesion problems can result from a build up of moisture in the skin/PIBPSA interface. Use of a solid material, i.e., one that is not porous,but that is otherwise permeable to water, such as a thin, e.g., 1 mil(i.e., 0.001 inch), polyurethane film, can be used. However, a porousmaterial such as a foam or fabric will, in general, better retain itsshape and provide good adhesion.

The present invention is not limited to the embodiments described andexemplified above, but is capable of variation and modification withinthe scope of the appended claims. Published patent applications andpatents referenced in this specification are incorporated herein byreference as though fully set forth.

1. A method of preventing pregnancy in a woman that comprises, during aneight week or a twelve week treatment cycle having a treatment intervalof seven weeks or eleven weeks and a rest interval of one week: (A)transdermally administering a contraceptively effective amount of aprogestin and an estrogen during the treatment interval by successiveapplications of transdermal hormone delivery devices; and (B)transdermally administering low dose progestin and low dose estrogenthroughout the rest interval by application of a transdermal hormonedelivery device; wherein, in a given woman or population of women: theamount of progestin delivered during the treatment interval results inan average progestin serum concentration level equivalent to at least500 pg/ml of levonorgestrel during the first week of the treatmentinterval and an average progestin serum concentration level equivalentto at least 750 pg/ml of levonorgestrel during the subsequent weeks ofthe treatment interval; the amount of estrogen delivered during thetreatment interval results in an average estrogen serum concentrationlevel equivalent to at least 15 pg/ml of ethinyl estradiol during thetreatment interval; the amount of the progestin delivered during therest interval results in an average progestin serum concentration thatis 25% to 75% of the amount of the progestin delivered during thetreatment interval; and the amount of the estrogen delivered during therest interval results in an average estrogen serum concentration that is25% to 75% of the amount of the estrogen delivered during the treatmentinterval.
 2. The method of claim 1, comprising: (A) transdermallyadministering the contraceptively effective amounts of the progestin andthe estrogen during the treatment interval by successive weeklyapplications of seven or eleven transdermal hormone delivery devices,one for each week of each treatment interval; and (B) transdermallyadministering the low dose progestin and low dose estrogen throughoutthe rest interval by application of a transdermal hormone deliverydevice during the rest interval.
 3. The method of claim 2, wherein eachdevice worn during the treatment interval provides a peak serum hormoneconcentration level after the patch is applied and a trough serumconcentration level at the time the patch is removed, the peak levelsbeing at least about 1.25 times trough levels.
 4. The method of claim 2,wherein the rest interval device has the same hormone concentrations asthe treatment interval device but is a fraction of the size of thetreatment interval device.
 5. The method of claim 2, wherein the restinterval device is the same size as the treatment interval device butcomprises reduced hormone amounts compared to the treatment intervaldevice.
 6. The method of claim 2, wherein: (a) the amount of progestindelivered during the rest interval is ¼, ⅓, ½, ⅔, or ¾ of the amountdelivered from each treatment interval device during the treatmentinterval; and (b) the amount of estrogen delivered during the restinterval is ¼, ⅓, ½, ⅔, or ¾ of the amount delivered from each treatmentinterval device during the treatment interval.
 7. The method of claim 1,wherein the rest interval device is worn during all of the restinterval.
 8. The method of claim 1, wherein the average progestin serumconcentration is equivalent to a serum concentration of at least about750 pg/ml of levonorgestrel during each treatment interval, optionallyexcluding all or a portion of the first treatment cycle, in a givenwoman or in a population of women.
 9. The method of claim 1, wherein theaverage estrogen serum concentration is equivalent to a serumconcentration of about 15 to about 65 pg/ml of ethinyl estradiol duringeach treatment interval, in a given woman or in a population of women.10. The method of claim 1, wherein (1) the progestin is levonorgestrelor the estrogen is ethinyl estradiol, or (2) the progestin islevonorgestrel and the estrogen is ethinyl estradiol.
 11. A kitcomprising: (a) seven or eleven, or a multiple of seven or eleven,transdermal hormone delivery treatment devices, each treatment devicecomprising a progestin and an estrogen in an amount sufficient to reducethe risk of pregnancy, each being intended for wear for one week; (b)one rest interval device for each seven or eleven treatment devices,intended for wear during a one week rest interval between successiveseven-week or eleven-week treatment intervals, wherein the rest intervaldevice comprises: (1) low dose progestin in an amount sufficient todeliver an average progestin serum concentration that is 25% to 75% theamount of the progestin delivered during each week of the treatmentinterval, and (2) low dose estrogen in an amount sufficient to deliveran average estrogen serum concentration that is 25% to 75% the amount ofthe estrogen delivered during each week of the treatment interval; and(c) instructions for use of the devices in an eight-week or atwelve-week treatment cycle comprising a seven-week or an eleven-weektreatment interval and a one-week rest interval.
 12. The kit of claim11, wherein each treatment device is formulated to generate a peak serumhormone concentration level after the patch is applied and a troughserum concentration level at the time the patch is removed, the peaklevels being at least about 1.25 times trough levels.
 13. The kit ofclaim 11, wherein the rest interval device has the same hormoneconcentrations as the treatment device but is a fraction of the size ofthe treatment device.
 14. The kit of claim 11, wherein the rest intervaldevice is the same size as the treatment device but comprises reducedamounts of estrogen and progestin compared to the treatment device. 15.The kit of claim 11, wherein the treatment device and the rest intervaldevice are formulated such that: (a) the amount of progestin deliveredduring the rest interval is ¼, ⅓, ½, ⅔ or ¾ of the amount delivered fromeach treatment interval device during the treatment interval; and (b)the amount of estrogen delivered during the rest interval is ¼, ⅓, ½, ⅔or ¾ of the amount delivered from each treatment interval device duringthe treatment interval.
 16. The kit of claim 11, in which the treatmentdevice is formulated to deliver an average progestin serum concentrationequivalent to a serum concentration of at least about 750 pg/ml oflevonorgestrel during each treatment interval, optionally excluding allor a portion of the first treatment cycle, in a given woman or in apopulation of women.
 17. The kit of claim 11, in which the treatmentdevice is formulated to deliver an average estrogen serum concentrationequivalent to a serum concentration of about 15 to about 65 pg/ml ofethinyl estradiol during each treatment interval, in a given woman or ina population of women.
 18. The kit of claim 11, wherein (1) theprogestin is levonorgestrel or the estrogen is ethinyl estradiol, or (2)the progestin is levonorgestrel and the estrogen is ethinyl estradiol.